Vascular conditions constitute a major health problem, particularly in western countries. Vascular conditions include heart conditions, peripheral vascular disease and cerebrospinal vascular conditions.
A major proportion of these conditions result from a lack of supply of blood to the respective tissues which thus are either chronically or acutely deprived of necessary levels of oxygen and nutrients. Typically these conditions result in ischemias where there has been blockage of the blood vessel by build up of, for example, plaque or physical blood vessel damage such that these are either blocked or constricted.
Heart conditions are perceived as the most prominent vascular disease. About 11 million adults in the United States of America (1995) had coronary heart disease, that however is out of a total of about 60 million adults with cardiovascular disease. Other vascular conditions thus affect a greater number of adults.
A relatively common cerebrovascular condition can manifest as a stroke, where an occlusion can lead to an acute attack. A gradual diminution of supply may also lead to decreased capacity of the brain to function and it has been postulated that such conditions may be associated with the onset of certain dementias.
Peripheral vascular disease are associated with a number of conditions, for example, as a complication of diabetes where a typical inadequacy of the microcirculation depletes supply to the extremities particularly the feet and legs of oxygen and nutrients.
Another example of reduced localized supply can occur with the treatment of various wounds including severe burns or chronic wounds such as bed sores. Chronic wounds are difficult to heal, partly due to an insufficient vascular bed supply of nutrient and healing compounds.
Scar formation may also be exacerbated because the healing process often involves a highly fibrotic tissue forming within minimal blood vessel formation. Scar formation is also a difficulty associated with achieving an adequate vascular supply in circumstances where a prosthesis or other implant is surgically position in a human tissue. An inadequate blood supply to the interface between the implant and the surrounding tissue can lead to medical complications and necrosis. This is of far more noticeable relevance where the implant is intended as a long term slow release depot of for example a pharmaceutical.
Treatment of myocardial ischemias are probably the most advanced of current treatments of vascular conditions. Present treatments include pharmacological therapies, coronary artery bypass surgery and percutaneous revascularization using techniques such as balloon angioplasty. Standard pharmacological therapy to aims either increase blood supply to the heart muscle or decreasing the demand of the heart muscle for oxygen and nutrients. Increased blood supply to the myocardium by relaxation of smooth muscle is achieved by administering agents such as calcium channel blockers or nitroglycerin. Decreased demand of the heart muscle for oxygen and nutrients is accomplished either by agents that decrease the hemodynamic load on the heart, such as arterial vasodilators, or those that decrease the contractile response of the heart to a given hemodynamic load, such as β-adrenergic receptor antagonists. Surgical treatment of ischemic heart disease is based on the bypass of diseased arterial segments with strategically placed bypass grafts. Percutaneous neovascularization is based on the use of catheters to reduce the narrowing in diseased coronary arteries. All of these strategies are used to decrease the number of, or to eradicate, ischemic episodes, but all have various limitations, and particularly the pharmaceutical approach can have severe side effects.
Preliminary reports describe new vessel development in the heart through the direct injection of angiogenic proteins or peptides. The several members of the fibroblast growth factor (FGF) family (namely acidic fibroblast growth factor, aFGF; basic fibroblast growth factor, bFGF; fibroblast growth factor-5, FGF-5 and others) have been implicated in the regulation of angiogenesis during growth and development. Gene therapy has been suggested by Hammond et al in U.S. Pat. No. 5,792,453 as a delivery mechanism for these angiogenic compounds.
Another suggested approach to promoting new blood vessel formation for treatment of vascular conditions is the administration of stem cells which can differentiate and give rise to cells required for such blood vessels to form. One problem associated with this approach is that it is not entirely clear which progenitor cells are responsible for formation of blood vessel, or whether indeed more than one cell type is required or whether other angiogenesis promoters are required.
One reported approach described in U.S. Pat. No. 5,980,887 (to Isner et al) has resulted from the isolation of an endothelial progenitor cell and the discovery that such cells play a role in blood vessel formation.
Numerous attempts at isolating and enriching mesenchymal precursor cells have been made because of the potential that these cells have for medicinal use. Pittinger et al., (1999) show the expansion of clonogenic cells from bone marrow and describes a preparation of enlarged mesenchymal stem cells. A more recent example of such a method providing for a relatively high yield from bone marrow is disclosed in publication WO01/04268 to Simmons et al. Neither of these reported mesenchymal cells were indicated as being capable of regeneration vascular lineages of cells capable of leading to blood vessel formation.
To date however there have been no examples of isolated mesenchymal precursor cells capable of forming vascular tissues in vivo.